Seeinstructions): A major emphasis of the Wisconsin ADRC is identifying features and avenues for early intervention in the preclinical state of AD. Project 1 of the Wisconsin ADRC is about early characterization of AD using a fibrillar amyloid positron emission tomography imaging method with Pittsburgh Compound B [C11]PiB. We seek to determine the relationship between amyloid binding measured with PiB,and neural activity where neural activity is indexed by a) cognitive function/decline, b) BOLD activity during a memory task, and c) resting cerebral blood flow (CBF) imaging in a cohort of cognitive decliners at high risk for AD. The overall hypothesis is that fibrillar amyloid binding to [C11JPIB will be related to markers of neural function in cognitive decliners at high risk for AD. We will focus on the posterior cingulate/precuneus brain region (which is known to have high amyloid burden in AD) and probe this region with 1) a functional MRI task previously shown to activate the region, 2) resting cerebral blood flow (CBF) using a whole-brain pseudo- continuous arterial spin labeling technique (ASLCBF),and [C11]PIB imaging. Specific Aim 1: To determine whether PIB binding in the posterior cingulate is associated with cognitive decline to MCI in a cohort of subjects who we have followed over a 4-year interval. Furthermore we will determine whether PIB binding in the posterior cingulate predicts subsequent decline. Specific Aim 2: To determine whether PIB binding in the posterior cingulate is associated with imaging markers of neural function (BOLD fMRI during a memory task, and resting cerebral blood flow). Specific Aim 3: To determine if the relationship between PIB binding in the posterior cingulate is related to cerebral spinal fluid levels of amyloid-beta42 andtau. To accomplish these aims we will identify 30 subjects who have declined over the prior four years to MCI and match them to 30 cognitively-stable subjects over the same interval. All will participate in a single study visit to include PiB,fMRI, ASL CBF, and a lumbar puncture for CSF collection. All will be subsequently followed annually by the Clinical Core of the Wisconsin ADRC to determine their cognitive status including decline to AD. The data collected in this project will be analyzed to determine the relationship of PiB with prior and subsequent cognitive decline and imaging markers of neural function using voxel-wise statistics. RELEVANCE (Seeinstructions): By the time a patient exhibits symptomatic dementia, devastating neural loss has already occurred. New methods for characterizing brain dysfunction are needed to facilitate early detection and early intervention. By applying advanced imaging to a well-characterized high-risk longitudinally-followed cohort, we are in a unique position to provide a greater understanding of early brain changes that occur in prodromal AD.